TY - JOUR
T1 - Potent 1,2,4-Triazino[5,6 b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis
AU - Ngo, Huy X.
AU - Green, Keith D.
AU - Gajadeera, Chathurada S.
AU - Willby, Melisa J.
AU - Holbrook, Selina Y.L.
AU - Hou, Caixia
AU - Garzan, Atefeh
AU - Mayhoub, Abdelrahman S.
AU - Posey, James E.
AU - Tsodikov, Oleg V.
AU - Garneau-Tsodikova, Sylvie
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/6/8
Y1 - 2018/6/8
N2 - A common cause of resistance to kanamycin (KAN) in tuberculosis is overexpression of the enhanced intracellular survival (Eis) protein. Eis is an acetyltransferase that multiacetylates KAN and other aminoglycosides, rendering them unable to bind the bacterial ribosome. By high-throughput screening, a series of substituted 1,2,4-triazino[5,6b]indole-3-thioether molecules were identified as effective Eis inhibitors. Herein, we purchased 17 and synthesized 22 new compounds, evaluated their potency, and characterized their steady-state kinetics. Four inhibitors were found not only to inhibit Eis in vitro, but also to act as adjuvants of KAN and partially restore KAN sensitivity in a Mycobacterium tuberculosis KAN-resistant strain in which Eis is upregulated. A crystal structure of Eis in complex with a potent inhibitor and CoA shows that the inhibitors bind in the aminoglycoside binding site snugly inserted into a hydrophobic cavity. These inhibitors will undergo preclinical development as novel KAN adjuvant therapies to treat KAN-resistant tuberculosis.
AB - A common cause of resistance to kanamycin (KAN) in tuberculosis is overexpression of the enhanced intracellular survival (Eis) protein. Eis is an acetyltransferase that multiacetylates KAN and other aminoglycosides, rendering them unable to bind the bacterial ribosome. By high-throughput screening, a series of substituted 1,2,4-triazino[5,6b]indole-3-thioether molecules were identified as effective Eis inhibitors. Herein, we purchased 17 and synthesized 22 new compounds, evaluated their potency, and characterized their steady-state kinetics. Four inhibitors were found not only to inhibit Eis in vitro, but also to act as adjuvants of KAN and partially restore KAN sensitivity in a Mycobacterium tuberculosis KAN-resistant strain in which Eis is upregulated. A crystal structure of Eis in complex with a potent inhibitor and CoA shows that the inhibitors bind in the aminoglycoside binding site snugly inserted into a hydrophobic cavity. These inhibitors will undergo preclinical development as novel KAN adjuvant therapies to treat KAN-resistant tuberculosis.
KW - aminoglycoside resistance
KW - antitubercular agent
KW - combination therapy
KW - high-throughput screen
KW - structure-activity relationship (SAR)
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U2 - 10.1021/acsinfecdis.8b00074
DO - 10.1021/acsinfecdis.8b00074
M3 - Article
C2 - 29601176
AN - SCOPUS:85048251988
VL - 4
SP - 1030
EP - 1040
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 6
ER -
